Despite decades of research that have led to an understanding of many causes of epilepsy and yielded over fifteen new antiseizure drugs and novel non-drug therapies, there remain no treatments that prevent epilepsy, nor are there ways to identify and prove such treatments. A major obstacle to research in this area is the fact that studies from single institutions are inadequate to answer the most important questions. The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is a large, international, multicenter Center without Walls (CWOW) to address this pressing need by using studies of animals and patients with traumatic brain injury (TBI) leading to post-traumatic epilepsy (PTE) to develop the techniques and patient populations necessary to carry out future cost effective full-scale clinical trials of epilepsy prevention therapies.

This is a project designed to facilitate the development of antiepileptogenic therapies by removing barriers and promoting large-scale collaborative research efforts by multidisciplinary teams of basic and clinical neuroscientists with access to extensive patient populations, well-defined and rigidly standardized animal models, and cutting-edge analytic methodology. We focus on antiepileptogenesis in PTE following TBI as this condition offers the best opportunity to determine the time of onset of the epileptogenic process in patients.

The EpiBioS4Rx Scientific Premise is: Epileptogenesis after TBI can be prevented with specific treatments; the identification of relevant biomarkers and performance of rigorous preclinical trials will permit the future design and performance of economically feasible full-scale clinical trials of antiepileptogenic therapies. Based on the work from a P20 planning grant, our program will consist of the following: (1) identify biomarkers of epileptogenesis in our animal model and in patients, (2) Develop and utilize a standardized platform for preclinical trials of potential antiepileptogenic (AEG) drugs, (3) Identify 1 or more lead antiepileptogenic drugs for a future interventional clinical trial, (4) Establish a network of advanced TBI centers capable of carrying out future clinical trials featuring our lead antiepileptogenic drugs used in the context of a personalized, medicine-based approach utilizing our panel of biomarkers, and (5) Develop and incorporate a public engagement program involving the mutual education and collaboration of consumers, consumer organizations and professionals to design and execute future large-scale interventional clinical trials of antiepileptogenic therapies.

DATA COLLECTION, ANALYSIS AND TRIAL DESIGN

Study Design

We have chosen to focus on disease prevention, but results of our efforts could also inform approaches to disease modification. We plan a translational, international, multiple project, multicenter, multidisciplinary approach to: 1) identify biomarkers of epileptogenesis in our animal model and in patients, 2) develop a standardized protocol for preclinical trials of potential antiepileptogenic therapies and identify one or more potential antiepileptogenic agent, and 3) create open shared resources for the entire epilepsy research community, including an epilepsy specific bioinformatics platform and database, a robust animal model of TBI leading to PTE, a standardized preclinical protocol for the evaluation of novel antiepileptogenic therapies, a network of TBI centers capable of carrying out future clinical trials of potential antiepileptogenic interventions, and a public engagement program committed to recruitment and retention. We anticipate this work will result in one or more candidate antiepileptogenic treatments at the end of the 5-year funding period, as well as the biomarker information, resources, expertise, and patient population to carry out an economically feasible, full-scale clinical trial.

1) Identification of biomarkers and epileptogenesis in animals and patients: Even if a potential antiepileptogenic agent existed, there is no at-risk patient population in which to test its success cost effectively. We have created a collaborative multicenter, international research effort composed of multidisciplinary teams of basic and clinical neuroscientists with access to robust, well-defined animal models, extensive patient populations, standardized protocols, and cutting-edge analytic methodology. We expect that the predictive power will likely require a combination of electrophysiological, neuroimaging, and biochemical biomarkers measured at different post-injury time points, to diagnose with high sensitivity and specificity ongoing epileptogenesis independent of the severity of brain damage. We anticipate these studies will also provide insights into the fundamental neuronal mechanisms of these processes and inform basic research into novel targets for antiepileptogenic interventions.

2) Standardized preclinical trials of potential antiepileptogenic therapies and identification of one or more potential antiepileptogenic agents: Scientific evidence suggests that many compounds could have antiepileptogenic potential, but adequate evidence to justify a clinical trial is lacking, in large part due to failure to reproduce promising results in more than one laboratory and difficulty translating the preclinical to the clinical condition. This failure reflects the absence of a valid animal model of human epileptogenesis and a standardized preclinical trial protocol, which adheres to the same rigid criteria used for clinical trials. We have developed a robust standardized fluid percussion injury (FPI) rat model of TBI leading to PTE in our laboratories that replicates epileptogenesis following TBI in patients with moderate to severe TBI and have been carrying out parallel reiterative animal/human studies. We will use this model also to create a rigorous standardized protocol for testing potential antiepileptogenic therapies utilizing a double-blind randomized approach and the therapy-specific biomarkers as they become available in a manner that is reproducible in any laboratory that follows the standardized protocol. We anticipate that the identification and validation of antiepileptogenic treatments in the preclinical trials using the profile of identified biomarkers from the parallel animal/human research paradigms, together with the establishment of a network of TBI centers with appropriate facilities and expertise will enable preparation for a future, economically feasible, cost-effective, full-scale, clinical trial of safety and efficacy of antiepileptogenic therapies to prevent PTE.

3) Creation of open and shared resources for the entire epilepsy community: A key to the success of large multidisciplinary research efforts that generate “big data” is an effective shared bioinformatics approach to data storage and analysis. With the EpiBioS4Rx P20 planning grant, we have succeeded in developing a multimodality, interactive, open access bioinformatics platform specific for epilepsy and are using this resource to carry out our studies. We have achieved this short-term goal in part by leveraging programs already supported by NIH and other funding sources. We have unified the functionality between the International Electrophysiology Web Portal (iEEG.org) platform of Dr. Brian Litt, who will be providing his expertise as a consultant, and the Laboratory of Neuroimaging (LONI) platform of Dr. Arthur Toga. The latter has supported extensive studies of biomarkers and treatments for Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, the genetic basis of aspects of hippocampal structure, and the exploration of computational genomics challenges. We are currently applying our bioinformatics algorithms to available animal and human electrophysiological and imaging data, and are collecting molecular, cellular, and other data to be integrated into this analytic process. Dr. Vespa from UCLA has recruited 13 TBI centers that will follow patients for two years to participate in our proposed clinical biomarker project. They will constitute a network with the facilities and expertise to perform the subsequent clinical trials once they are justified by preclinical studies and made feasible by biomarker identification. For the design of the future clinical trials, we developed an extensive public outreach program of epilepsy and TBI consumer groups committed to recruitment and retention of subjects and consumer satisfaction. We plan to make available to the greater epilepsy community all of our bioinformatics tools and resources, databank, biobank, experimental protocols for a standardized TBI/PTE animal model and preclinical evaluation of antiepileptogenic therapies, a network of TBI centers with facilities and expertise to carry out future clinical trials of antiepileptogenic interventions. To this end, collaborations have been established with a number of related programs, including Epi4K, EpGP, EPITARGET, FEBSTAT, TRACK-TBI, CENTER-TBI, ADAPT, CSR, and the VA Epilepsy Centers of Excellence to expand the patient population available for future clinical trials.

Core Interactions

Specific Aims

Specific Aim 1: Carry out focused multicenter, collaborative, preclinical and clinical investigations to identify and validate biomarkers of Epileptogenesis following TBI and preclinical investigations to evaluate potential interventions that prevent the development of PTE as well as their effects on the identified biomarkers of epileptogenesis in a standardized animal model of TBI/PTE.

Research Project 1: Animal studies at 3 centers using a standardized lateral fluid percussion injury rat model of PTE to identify plasma, imaging, and electrophysiological biomarkers measured at different post-injury time points, alone or in combination, to diagnose with high sensitivity and specificity ongoing epileptogenesis independent of the severity of brain damage.

Research Project 2: Animal studies at 4 centers to identify targets and biomarkers for treatment implementation, which in combination with the biomarkers of epileptogenesis from Project 1, will guide rigorous randomized preclinical trials of potential AEG interventions to prevent PTE in the standardized animal model of TBI/PTE.

Research Project 3: Clinical/translational studies at 13 experienced TBI centers will identify biomarkers and validate in humans the biomarkers identified in Projects 1 and 2.

Specific Aim 2: Our multi-modal epilepsy-specific bioinformatics approaches will be applied to the results obtained in Projects 1, 2, and 3 to derive a combination of biomarkers that will reliably predict epileptogenesis following TBI in both animals and humans and identify specific AEG treatments to be used in future clinical trials. Following the completion of the aims, and in partnership with the consumer and scientific groups in the Public Engagement Core, our approach will permit the design and execution of a feasible, cost-effective, personalized medicine-focused, interventional, randomized, international clinical trial for AEG therapies in TBI.

Innovation

EpiBioS4Rx is a unique translational project. It brings together human and animal epileptogenesis research on TBI with active participation of consumer advocates to provide all the necessary information, resources, expertise, and patient population to carry out an economically feasible, full-scale clinical trial of one or more antiepileptogenic therapies at the end of the 5 year funding period.

EpiBioS4Rx has integrated existing interactive multimodality bioinformatics platforms. The unique combined platform is capable of acquiring, storing, and analyzing electrophysiological, imaging, molecular, and cellular data from animal and clinical studies that have not been used to study epileptogenesis previously, and that will constitute an open-access, epilepsy-specific database and analytics resource.

EpiBioS4Rx will develop the first validated multimodal biomarker panel for preclinical and clinical antiepileptogenesis trials.

EpiBioS4Rx will develop the first rigorous preclinical multicenter therapy-development pipeline for promising antiepileptogenic treatments to facilitate their testing in a future antiepileptogenesis clinical trial in patients with TBI. We propose to screen 5 treatment protocols for their effect on modifying PTE biomarkers in our animal model of TBI, test the leading compound for its efficacy in preventing PTE and thus prepare for a future clinical trial of the leading compound.

EpiBioS4Rx will identify at least one compound that shows an anti-epileptogenic effect in a rigorous, long-term, multicenter pre-clinical trial that is ready to proceed to be tested in a clinical trial utilizing the EpiBioS4Rx clinical TBI centers and biomarkers.

EpiBioS4Rx has enlisted the enthusiastic participation of 13 advanced clinical TBI programs. These programs have not studied epilepsy as part of their research in the past, will use the data from their extensive subject populations to identify likely biomarkers of epileptogenesis, will validate biomarkers identified in animal TBI studies, and will establish a network of advanced TBI centers with continuous EEG monitoring and other resources, expertise, and patient populations to carry out future full-scale clinical trials of antiepileptogenic agents identified in this study or others.

EpiBioS4Rx will utilize common data elements, and a rigorously designed, standardized protocol for preclinical trials of potential antiepileptogenic agents. This unique paradigm will employ therapy specific biomarkers identified in animal and human studies to identify one or more antiepileptogenic agents for full-scale clinical trials.

Our Public Engagement Core will, for the first time, bring together epilepsy and TBI advocacy and consumer groups to address common interests and concerns. This effort will not only involve patients with PTE but also patients at risk for developing PTE and will facilitate recruitment and retention of subjects for future clinical trials.

EpiBioS4Rx has developed a Charter and Publication Policy that not only establishes a code of equity among investigators but also outlines how our data, tools, and resources will be made available to the entire epilepsy community.

Infrastructure

EpiBioS4Rx has developed an extensible, portable and robust infrastructure which includes a database portal to a distributed federated architecture, a graphical framework for computational data processing via web-application clients and back-end Grid servers, and secure access control to data and services, utilizing reliable hardware resources (storage, processing and networking).

The informatics approach of this antiepileptogenetic study will involve management of heterogeneous data, data mining, exploratory data analysis, modeling, and interrogation of multimodal and multiform datasets. Specifically, the data that we will manage, process and disseminate includes proteomics data, genomics data, EEG, multichannel volumetric neuroimaging data, neurocognitive and behavioral data for patients as well as data from a diverse array of epileptogenetic animal models.

Data Federation

To enable rapid development and utilize all existing infrastructure we intend to design an efficient data federation architecture that facilitates the traversal, discovery, upload and retrieval of the imaging, genetics, clinical, demographic and behavioral data to/from all distributed and heterogeneous data sources provide by the participating institutions. This approach will utilize the available database services and leave current dataset in place avoiding data redundancy. This data federation approach will support standard data operations using an integrated virtual portal view where the real data is stored in multiple diverse sources; however it will be accessible via one centralized location. The original data sources will remain under the control of each hosting institution and data will be pulled, queried and retrieved on demand via the federated portal access.

Hardware Infrastructure

We have a significant hardware infrastructure that provides high performance, security and reliability. The fault-tolerant network infrastructure has no single points of failure having multiple switches, routers and Internet connections. A firewall appliance protects and segments the network traffic, permitting only authorized ingress and egress through. Multiple redundant database, application and web servers ensure service continuity in the event of a single system failure and also provide improved performance through load balancing of requests across the multiple machines. To augment the network-based security practices and to ensure compliance with privacy requirements, the servers utilize SSL encryption for all data transfers. Client-side de-identification of files using a signed applet integrated into the software ensures that only de-identified data is transmitted to the servers. Post-transfer redundancy checking on the files is performed to guarantee the integrity of the data. To date, we have neither suffered a system disaster, nor lost data; however as an added layer of security, sophisticated backup mechanisms are in place to protect the integrity of data.

Research & Data Analysis

Streamlined Data Consolidation: Users will be able to upload their raw data files directly to an extended version of the LONI infrastructure where they will automatically be classified, converted, and annotated. By automating much of this process, researchers both uploading and downloading data will be spared the time and effort currently involved in accessing and sharing epilepsy data. This streamlined data consolidation will increase the financial efficiency and scientific productivity of the CWOW and the broader epilepsy research community. In addition, physical samples will be brought together in a single biobank, further reducing coordination challenges. Much of these data have already been collected by the PIs presenting this proposal; however, the huge size of these data combined with the many different file formats makes effective navigation currently frustratingly labor-intensive and error-prone.

User-friendly data search and navigation: By converting data to consistent file formats and tagging that data with metadata, the CWOW will enable Google-style search of all available epilepsy data. However, because data will be interlinked and co-registered across data sets and modalities, the search functionality will not simply match data against individual items like Google—rather, it will find interlinked combinations of data (even across modalities and data sources) that match the desired criteria. This enables sophisticated custom searches that match the functionality of predefined query forms. Users will be able to browse data in its most appropriate visual representation and pivot from one data view or modality to another. Through our experiences with LONI, we have learned the access control and sharing mechanisms required by the community and how effectively to enable inter-project as well as community-scale data sharing. Key components include giving users explicit access control for their data and results as well as providing project groups for larger-scale permissions management. Furthermore, comparable tools that can be repurposed were developed for LONI as part of our planning grant and projects like ADNI.

Automated analysis: The LONI Pipeline contains a common framework for visual and programmatic construction of data-driven workflows for electrophysiology, imaging, and biosample data. We will customize these tools to the study of epilepsy data. With the aid of LONI’s workflow builder, complex analyses are represented visually, further supporting researchers’ investigations. Examples of Pipeline applications include developing a unified coordinate space for seizure locations across organisms, using string similarity and value overlap to predict that different contributor metadata fields are the same, and providing graphical interfaces for linking data. Co-registration algorithms will typically be invoked at upload-time but may be triggered later manually for further refinement. The IAC will provide MRI supervision and integration from different scanners and centers by supervising phantom studies, assessing quality, and fixing problems with heterogeneity. While LONI has primarily used Pipeline for human data, it has also been used to study neural networks of the mouse neocortex. The CWOW would further expand these capabilities, providing robust workflow pipelines for both humans and animal models.

Iterative improvement using novel analytical tools: The sheer quantity of data and the noise inherent in the data necessitates the development of novel analytical tools, incorporating the most recently developed mathematical and statistical tools to discover previously undetected biomarkers. Dr. Bragin et al. recently discovered a novel biomarker, repetitive high frequency oscillations and spikes (rHFOSs). Dr. Gotman, a consultant on this project, has established tools to study the relationship between spikes and HFOs and showed their links to epileptogenesis. Dr. Duncan has developed sophisticated mathematical methods to analyze both animal and human data separately and for trans-species comparisons.

We are keenly aware of multiple conceptual and technical issues regarding data analyses with biomarkers, including within subject correlation, multiplicity, multiple clinical endpoints, and selection bias. Utilization of multiple statistical approaches will allow us to address these concerns in full.

Standardized sample collection, shipping, and biobank storage protocols: The project will define methods for harvesting, freezing, and storing tissue and other biosamples (i.e. serum). Data and tissue stored for collaborating preclinical trials, such as TRACK TBI, ALLO, PPMI, TRACKHD, ICBM, AIBL, ACE, ABIDE, 4RTNI, Mapp, and the Human Connectome Project already have these protocols in place with informatics provided by LONI. Animal protocols for storing parallel samples to humans will be stored and treated in a similar fashion to compare findings from parallel human and animal studies.

A data safety monitoring board (DSMB) will advise us as we perform a rigorous multicenter preclinical antiepileptogenesis trial using a blinded, vehicle-controlled randomized study design to determine the antiepileptogenic effect of the lead compound. The results of the three projects integrated with the IAC, following the close guidance of the DSMB, will assist in planning the optimal design of a future clinical antiepileptogenesis trial for successful drugs.

People

Who's who?

EpiBioS4Rx is a federated consortium of international research centers. Each component of EpiBioS4Rx is multicenter with multiple autonomous investigators.